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Published 9 December 2002. doi:10.1083/jcb.200209011
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© The Rockefeller University Press, 0021-9525/2002/12/747 $5.00
The Journal of Cell Biology, Volume 159, Number 5, 747-752

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 BDNF-induced TrkB activation down-regulates the K+–Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion

Claudio Rivera1,2, Hong Li1,2, Judith Thomas-Crusells2, Hannele Lahtinen1, Tero Viitanen1, Avtandil Nanobashvili3, Zaal Kokaia3, Matti S. Airaksinen2, Juha Voipio1, Kai Kaila1 and Mart Saarma2

1 Department of Biosciences, Division of Animal Physiology
2 Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
3 Section for Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, 221 84 Lund, Sweden

Address correspondence to Claudio Rivera, Institute of Biotechnology and Division of Animal Physiology, Viiki Biocenter, PO Box 56, Viikinkaari 9, FIN-00014 University of Helsinki, Finland. Tel.: 358-9-191-59359. Fax: 358-9-191-59560. E-mail: rivera{at}operoni.helsinki.fi

Pathophysiological activity and various kinds of traumatic insults are known to have deleterious long-term effects on neuronal Cl- regulation, which can lead to a suppression of fast postsynaptic GABAergic responses. Brain-derived neurotrophic factor (BDNF) increases neuronal excitability through a conjunction of mechanisms that include regulation of the efficacy of GABAergic transmission. Here, we show that exposure of rat hippocampal slice cultures and acute slices to exogenous BDNF or neurotrophin-4 produces a TrkB-mediated fall in the neuron-specific K+–Cl- cotransporter KCC2 mRNA and protein, as well as a consequent impairment in neuronal Cl- extrusion capacity. After kindling-induced seizures in vivo, the expression of KCC2 is down-regulated in the mouse hippocampus with a spatiotemporal profile complementary to the up-regulation of TrkB and BDNF. The present data demonstrate a novel mechanism whereby BDNF/TrkB signaling suppresses chloride-dependent fast GABAergic inhibition, which most likely contributes to the well-known role of TrkB-activated signaling cascades in the induction and establishment of epileptic activity.

Key Words: chloride homeostasis; neurotrophic factors; GABAA depolarization; inhibition; hippocampus


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